The overall goals of the research program involve a comprehensive approach to the adaptations in renal function that occur in the transition from health to end stage chronic renal disease. The studies will be directed towards an examination of both the intrarenal and extrarenal events that are involved in and allow for these adaptations to occur. The experimental approach extends to an examination of the nature of the biologic control systems that permit the continued maintenance of external balance and homeostasis for many of the key solutes of body fluids in the face of progressive nephron loss. The opportunity to study the component parts of such control systems is greatly enhanced in chronic renal disease due to the fact that any given perturbation of body fluids (imposed by the addition of a fixed amount of any solute) leads to an excretory response per nephron for that solute that increases progressively as the nephron population decreases progressively. Moreover, the information that can be gained from the study of biologic control systems in uremia may have major impact on the understanding of the regulation of body fluids in health and of the aberrations that take place in a variety of non-uremic clinical disorders of body fluids. Major emphasis will be given to the sodium (or volume) control system and to the possibility that a natriuretic hormone may play a central role in modulating sodium excretion. The possibility that effector elements of control systems, such as natriuretic hormone, parathyroid hormone, etc, may have deleterious effects on extrarenal organs in advancing renal disease, when concentrations become high, will also be examined.